Seizure Management, Part 1: When to Start Anti-epileptic Drugs

This is the first article in a series of two articles addressing management of seizures. A link to the second article is provided below:

Seizure Management, Part 2 โ€“ Treating a Seizure with Anti-Epileptic Drugs

Provoked versus Unprovoked Seizures

One of the first questions a clinician must answer when confronted with a patient with seizures is whether the seizure was provoked or unprovoked. Provoked seizures typically have an identifiable cause such as metabolic disturbances, drug intoxication and withdrawal, stroke, intracerebral hemorrhage, trauma or malignancy. Each of these categories of provoked seizure carries separate recommendations for when to start and stop antiepileptic drugs (AEDs) and is addressed separately below.

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Seizures Provoked by Metabolic Disturbance

Multiple metabolic disturbances can cause seizures. Examples include alcohol/drug withdrawal and intoxication, hyponatremia, hypernatremia, hypomagnesemia, hypocalcemia, hypoglycemia, non-ketotic hyperglycemia, uremia, hypoxia, hyperthyroidism, dialysis disequilibrium syndrome and porphyria. Such seizures have a high risk for recurrence in the acute period of metabolic derangement and hospitalization. However, the potential for late seizure recurrence and development of future epilepsy is felt to be low. It is reasonable, therefore, to consider short term anti-seizure medication in the acute setting if the metabolic derangement is expected to be prolonged or the seizure lasts more than 2 minutes.

Seizures Provoked by Ischemic or Hemorrhagic Stroke

Seizures are a common sequela of stroke. According to the Seizure after Stroke Study, 8.6% of ischemic stroke patients and 10.6% of hemorrhagic stroke patients had seizures. The incidence of seizures is increased with cortical and large volume strokes.

Early onset seizures are typically defined as occurring within two weeks of a stroke, and late onset seizures occur after 2 weeks. 90% of patients develop epilepsy (recurrent seizures) after a late-onset seizure, while only 30% of patients develop epilepsy after an early onset seizure. This is thought to occur because early onset seizures in the acute phase of stroke are caused by a temporary metabolic dysfunction induced by ischemia, whereas late-onset seizures result from a more permanent state of brain gliosis and scarring.

Multiple early onset seizures or early onset status epilepticus should be treated with anticonvulsants for three months or longer. Anticonvulsant treatment for a single early onset seizure after stroke is controversial, however. One suggested approach is to treat a single early onset seizure after stroke with an anticonvulsant initially but discontinue the medication if the EEG shows no epileptiform discharges at the time of hospital discharge. In cases of late-onset seizure after stroke, the incidence of epilepsy is 90%, and these patients are usually treated with lifelong anticonvulsants.

There is an overall lack of rigorous data regarding the particular AED to start in post-stroke seizures. In one randomized prospective study (Gilad, et al) lamotrigine was better tolerated than carbamazepine in a post-stroke seizure. Lamotrigine also appeared to be more efficacious than carbamazepine, but this finding did not reach statistical significance. In another uncontrolled study, Alvarez-Sabin et al found gabapentin to be useful and safe for late poststroke seizures with 80% seizure remission.

Seizures Provoked by Traumatic Brain Injury (TBI)

Seizures following head trauma (post-traumatic seizures) are usually defined as early when they occur within seven days of the head injury. Post-traumatic seizures are characterized as late when they occur after seven days. Early seizures have a low chance of recurrence, while late seizures result from more permanent structural brain abnormality and have a high chance of recurrence. This distinction is useful when considering the treatment of post-traumatic seizures.

Prophylaxis in Traumatic Brain Injury:

Prophylactic treatment with phenytoin should be started as soon as possible following severe traumatic brain injury to reduce the risk of early post-traumatic seizures in the first seven days of head trauma. Severe TBI is defined as intracranial hematoma, brain contusion on head CT, depressed skull fracture or prolonged loss of consciousness or amnesia. Prophylactic treatment should not be used beyond seven days from the time of head injury to reduce the risk of late post-traumatic seizures.

Treatment of Early Post-Traumatic Seizures:

Early post-traumatic seizures are often treated with phenytoin. Treatment is initiated because of the risk of status epilepticus, a risk of aggravating a systemic injury and to prevent the theoretical increase in intracranial pressure related to increased blood flow during repeated seizures. Anti-epileptic drugs are typically continued throughout the hospital stay but then gradually tapered within the first few weeks.

Treatment of Late Post Traumatic Seizures:

The risk of developing a second seizure after one late onset post-traumatic seizure is quite high. Haltiner et al found that the incidence of recurrent late seizures was 86% by 2 years from the time of head trauma. Given such a high chance of seizure recurrence, patients should be placed on an anticonvulsant medication after even a single late onset post-traumatic seizure.

Seizures Provoked by Primary or Metastatic Brain Tumor

Patients who have one or more seizures in the setting of a primary or metastatic brain tumor should be treated with antiepileptic medication. Newer AEDs such as levetiracetam, pregabalin, lamotrigine, lacosamide, or topiramate are typically used in this population of patients. These drugs tend to be safer and have fewer drug-drug interactions.

Patients with a primary or metastatic brain tumor who have NOT had a seizure do not require prophylactic antiepileptic drug (AED) therapy. However, prophylactic AED is suggested in patients who have not had a seizure but who are undergoing surgery for a brain tumor in the peri-operative setting. The medication can be slowly tapered about 1 to 2 weeks following surgery, and long-term therapy is not required if there are no seizures.

Unprovoked Seizures

Work Up:

The AAN Practice Parameter for First Seizure in Adults recommends that an EEG and brain imaging in the form of brain MRI or head CT should be considered as part of the routine evaluation of adults presenting with a first unprovoked seizure. A brain MRI is preferred over head CT unless acute brain hemorrhage is suspected. Brain imaging can identify a structural brain lesion such as a tumor, stroke, or cysticercosis with about 10% yield and has some value in determining the risk of seizure recurrence. EEG shows significant abnormalities predicting the risk of seizure recurrence in about 29% of cases. Laboratory tests such as blood counts, blood glucose, electrolyte panels (particularly sodium), lumbar puncture, and toxicology screening may be helpful depending on the particular clinical circumstances and are usually performed in the acute, often hospital, setting.

Management of a First Unprovoked Seizure:

The decision to start an anti-epileptic drug (AED) after a first unprovoked seizure rests on weighing the risk of seizure recurrence versus medication side effects. The risk of seizure recurrence after a first unprovoked seizure is greatest in the first 2 years ranging from 21% to 45%. Starting an AED immediately after a first unprovoked seizure is likely to reduce the risk of seizure recurrence in the first 2 years but is unlikely to improve sustained seizure remission over the long term beyond three years. Certain variables, however, are associated with an increased risk for seizure recurrence. These variables include 1. Prior brain insult including stroke, head trauma, CNS infection, cerebral palsy, and developmental cognitive disability 2. EEG showing epileptiform abnormality 3. Brain imaging structural abnormality felt to account for the seizure and 4. Nocturnal seizure. The risk of adverse events related to AEDs ranges from 7% to 31%, and these events are predominantly mild and reversible.

Overall, the decision of whether to start an AED after a first unprovoked seizure is complicated and should be based on weighing the risk of seizure recurrence against the risks of adverse events. Most clinicians would start an AED in patients with a first unprovoked seizure who are found to have an increased risk for seizure recurrence (prior brain insult, abnormal EEG, or brain imaging structural abnormality). On the other hand, patients without the above risk factors have a lower risk of seizure recurrence and waiting until a second unprovoked seizure to start an AED is reasonable in this circumstance. That said, patient preference is also an important part of the decision-making process. For example, if seizure recurrence risk is determined to be low but the patient places a high value on avoiding any recurrent seizures, starting an AED in this setting may be reasonable.

Two or More Unprovoked Seizures:

About 33% of patients with a first unprovoked seizure will have further seizures within five years. However, about 75% of patients with 2 or 3 unprovoked seizures have further seizures within four years. Given such a high rate of recurrence, patients presenting with 2 or more unprovoked seizures should be started on anti-seizure medication.

Seizure management is a complex issue. We have developed a comprehensive algorithm for the treatment of provoked and unprovoked seizures that can be accessed through Infera, our innovative Clinical Decision Support application. The information is evidence based and peer reviewed by board certified neurologists.

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